For more than 50 years, the tetracyclines have been used as antibiotics. An especially valuable member of the tetracycline family is doxycycline. This broad-spectrum antibiotic was first synthesised in 1962 and marketed by Pfizer under the name Vibramycin.RTM..
Doxycycline is available in several different salts: Doxycycline monohydrate, doxycycline hydrochloride (hyclate), doxycycline carrageenate, doxycycline calcium and doxycycline phosphate (fosfatex).
Doxycycline shares its mode of action with other tetracyclines: Inhibition of bacterial protein synthesis. The inhibition is established through inhibition of binding of aminoacyl-tRNA primarily to 70S ribosomes but also to 30S ribosomes. The inhibition only leads to a bacteriostatic effect of the tetracyclines including doxycycline. Tetracyclines are active against a broad range of both gram positive and gram negative bacteria, aerobes as well as anaerobes. In all cases examined, doxycycline was found as effective as tetracycline and for several bacteria even more effective than tetracycline (Cunha 1982). Bacterial resistance to tetracyclines are frequent both in vitro and in vivo, and the resistance is transferred by a plasmid. Due to the bacteriostatic effect of tetracyclines they usually can not be combined with other cell-cycle specific antimicrobial agents, as the resting cells do not change cell cycle.
Most tetracyclines are incompletely absorbed and their absorption is dependent on the concomitant food intake. Absorption of doxycycline is almost complete (73-95%) and independent of food intake (Saivin, 1988).
The pharmacokinetic parameters of the different salts (hyclate, monohydrate, carrageenate) of doxycycline do not significantly differ under standard conditions (Saivin 1988, Grahnen 1991) and several comparative studies are found in the literature.
Doxycycline undergoes enterohepatic recycling-as first suggested by Gibaldi 1967, and later confirmed in pharmacokinetic profiles obtained by Malmborg 1984 and Nguyen 1989. The secondary peak in serum concentration due to reabsorption occurs around 10 to 12 hours after administration. Not all reports on doxycycline pharmacokinetics note the secondary peak, this can either be due to the fact that few samples are collected around the time of the secondary peak or because the data presented is adjusted to a pharmacokinetic model, which does not take the enterohepatic recycling into account.
The relative long half life of doxycycline in combination with enterohepatic recycling leads to accumulation after multiple dosing of doxycycline. The terminal half life is up to 22 hours and therefore once a day dosage of doxycycline is possible (Schach von Wittenau 1974).
Two factors have been reported which influence the pharmacokinetics of doxycycline. The pH in the stomach (Grahn en 1991) and concomitant administration of oral antacids (Nguyen 1989).
An increased pH of the stomach (Bogardus 1979b) decreases the bioavailability of doxycycline monohydrate whereas doxycycline hyclate and doxycycline carrageenate dissociation and absorption are independent of pH.
The increased pH in the stomach after omeprazole administration is expected to slow down the dissolution of doxycycline monohydrate and thereby decrease its absorption.
The very long terminal half life of doxycycline is nicely demonstrated in the study of Nguyen 1989 where the 36 and 48 hours values has been performed in contrast to many other pharmacokinetic studies of doxycycline.
Doxycycline is lipophilic and is widely distributed in the tissues. High concentrations are found in renal tissue and gallbladder/bile. Therapeutic and relatively higher concentrations than those of ampicillin are-found in sinus secretions, palatine tonsils, nasal polyps and lung tissue (Cunha 1982, Saivin 1988). The Use of doxycycline in upper respiratory tract infections is therefore rational.
Doxycycline is not metabolised in humans (Saivin 1988). It is mainly excreted in faeces and approximately 20% can be recovered in urine. The doxycycline excreted in faeces is probably bound in a way that makes it inactive, as the intestinal flora is not affected by doxycycline treatment (Cunha 1982).
Doxycycline is generally reported to be well tolerated (Cunha 1982).
Doxycycline was first introduced into clinical practice in 1968 as the HCl salt, called doxycycline hyclate. This salt was formulated in tablets or capsules. However, it was soon shown that these formulations had serious side effects. In a study of adverse drug reactions from antibiotics, 35/113 (31%) of patients treated with doxycycline hyclate after questioning reported nausea and vomiting while 24/373 (6.4%) spontaneously reported nausea and vomiting. These frequencies where 3-fold higher than those reported with other antibiotics. The tendency of nausea and vomiting is probably elicited from the stomach.
Another side effect of doxycycline hyclate is esophageal ulceration, if the capsules for some reason do not reach the stomach but remain in the oesophagus.
A solution to these problems has been attempted by the introduction of doxycycline hydrate (base). This new formulation has eliminated the above mentioned side effects, but it soon became apparent that the bioavailability in a number of patients, which were also in treatment with antacids and the like, was significantly reduced.
This can be explained by the lack of acid production in the stomach being the cause of reduced dissolution of doxycycline hydrate.
Considering that a great deal of the population has elevated gastric pH caused by either achlorhydria or due to the intake of antacids, H2-blockers, omeprazazole or the like, antibiotic treatment with doxycycline hydrate gives an unacceptable low bioavailability.
One solution to this problem has recently been suggested by the introduction of doxycycline carrageenate, which has a satisfactory bioavailability in subjects with elevated gastric pH. In subjects with normal pH conditions in the stomach, the use of doxycycline carrageenate has no advantages due to the spontaneous cleavage of doxycycline carrageenate into doxycycline H and carrageenate ion.
A study of cats (EP 091 409) showed that doxycycline carrageenate does not result in oesophagus ulcerations. No human safety data has been found on doxycycline carrageenate. To the best of our knowledge, no or very few clinical studies have been performed with doxycycline carrageenate and therefore a specific side effect profile of this doxycycline salt is not available.
By using different pharmaceutical preparations of doxycycline, attempts have been made to achieve a controlled release effect.
One solution to the aforementioned problems is the use of film coated tablets. A formulation with doxycycline hyclate was developed with less tendency to disintegration in the oesophagus (Delphre 1989). An enteric coated pellet formulation of doxycycline (Doryx.RTM., Doxylets.RTM.) has been developed to prevent the total dose of doxycycline hyclate dissolving in a small area of the stomach. Such formulations have been shown to have a reduced (approximately 50% reduction) rate of nausea and vomiting (Khouzam 1987, Berger 1988, Story 1991) and an unchanged bioavailability (Williams 1990). A pellet formulation does not have an automatically unchanged bioavailability. In a doxycycline pellet formulation developed at the University of Nanking, China it was found that 200 mg of the pellet formulation were bioequvivalent to 100 mg of the standard doxycycline hyclate formulation (Qiu 1986).
Therefore, a need exists for a doxycycline formulation with controlled release properties.
The tetracyclines belong to a group of antibiotics which are manufactured by fermentation of various Streptomyces species. The most widely used are doxycycline, oxytetracycline, chlorotetracyclines and tetracycline. A number of semisynthetic tetracycline are known, for instance methacycline and minocycline. The most widespread of these semi-synthetic tetracyclines is .alpha.-deoxy-5-hydroxy-tetracycline (doxycycline), which is manufactured by a 3-step synthesis with oxytetracycline as the starting material as described in U.S. Pat. No. 3,200,149 to Pfizer (1965). In this patent, the hydrate and the hyclate are also disclosed.
U.S. Pat. No. 3,927,094 to Villax discloses the manufacture of alkali metal polymetaphosphate complexes of doxycycline; This salt is characterized by its high solubility in water.
In GB 2.088.864 to Villax, doxycycline mono-sodium-tetraphosphate is disclosed, which is also very water-soluble and has improved stability.
The sulfosalicylate of doxycycline is known from GB 1,305,860 to Alfa Farmaceutici. This salt is sparingly soluble in water and is used in the doxycycline manufacturing process. The sulfo-salicylic acid salt has no clinical use, as sulfosalicylic acid is not accepted for medicinal use.
In EP 91.409 Kabi Vitrum a complex between doxycycline and carrageenan is disclosed. Carrageenan is a sulphated polysaccharide with a molecular weight from 100,00 to 100,000. This complex is insoluble in water. By dissolution, it is shown that the doxycycline hydrocarrageenate complex releases the active substance at the same rate-as doxycycline hyclate in the gastric juice.
.beta.-D-fructofuranosyl-.alpha.-D-glucopyranoside octakis (hydrogen sulphate), referred to in the following as sucrose-octa-O-sulphonic acid, is produced by sulphating sucrose with sulphur trioxide in pyridine. In this process, eight hydroxy groups in sucrose are esterfied with eight molecules of sulphuric acid under the formation of semi-esters. Sucrose-octa-O-sulphonic acid forms well crystallized salts with Na, K, Cs, Rb and ammonium. (Ochi 1980)
Salts of this type are proposed for the treatment or prevention of lesions and/or inflammation of non-peptic ulcer nature in the digestive tract, according to WO 94/00476 to Bukh Meditech.
Thus, the only salt of the sucrose-octa-O-sulphonic acid, which is presently used in medical therapy is the aluminium salt produced by treatment of sucrose-octa-O-sulphonic acid with aluminium hydroxide (U.S. Pat. No. 3,432,489 to Chugai, 1969) and is known under the name sucralfate having the general formula C.sub.12 H.sub.54 Al.sub.16 O.sub.75 S.sub.8, 8H.sub.2 O (Morikawa, 1981).
Sucralfate is widely used in the treatment of gastric ulcers. Peroral administration of tablets, or a suspension causes sucralfate to react with the acidic gastric juice, under formation of a sticky gel, which adheres to the mucosa and forms a protective layer, especially on the ulcerated areas.
The effect of sucralfate is largely ascribed to the high content of aluminium hydroxide ions which act as acid neutralizers and absorb pepsin and bile salts. (Nagashima, 1981)
No other salts of the sucrose-octa-O-sulphonic acid have hitherto been found suitable for medical purposes.